Abstract 5209: Abrogation of STAT3 activation by JSI-124 enhances dasatinib-induced cytotoxicity in malignant human glioma cell lines

Abstract

Abstract Src family kinases (SFK) collectively regulate a variety of cellular functions in many cancer types including proliferation, invasion, motility, survival, differentiation, and angiogenesis. Src greatly enhances EGFR-mediated transformation, raising the possibility that Src and/or its related family members may be effectors of EGFR signaling in cancer, including in glioblastoma. Although Dasatinib (BMS-354825), an ATP-competitive, small molecule tyrosine kinase inhibitor, suppresses the activity of SFKs at nanomolar concentrations, IC50 values ranged from 7 to 30 µM for inhibition of proliferation, well above the clinically achievable range. Because Src kinases were initially implicated in STAT activation, we hypothesized that the combination of Src inhibitor dasatinib and JAK2/STAT3 inhibitor JSI-124 would promote glioma cytotoxicity by decreasing both the activation status of c-Src and STAT3, as well as downregulating the levels of other relevant signaling effectors. We, therefore, examined the effects of dasatinib and JSI-124, alone or in combination, on signal transduction, migration and apoptosis in a series of malignant human glioma cell lines. JSI-124 significantly enhanced the efficacy of dasatinib in vitro. Combination of dasatinib and JSI-124 displayed a significant inhibition of cell migration in all cell lines. The effects on cell migration correlated with the inhibition of Src and downstream mediators of adhesion (e.g. focal adhesion kinase). Cells exposed to dasatinib and JSI-124 induced morphological changes that were consistent with an upstream role for Src in regulating focal adhesion complexes. Taken together, targeting Src and STAT pathway may contribute to the treatment of cancers that demonstrate increased levels of EGFR, Src and STATs, including malignant human glioma Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5209.